Prominent degradative fragments of Cartilage oligomeric matrix protein (COMP), a noncollagenous Icomponent of the extracellular matrix, has been observed in arthritic diseases for several years and shows great promise as a biological marker of cartilage metabolism in arthritis. The molecular mechanism of COMP degradation and the enzyme(s) responsible for the production of COMP degraded fragments in patients, however, remain unknown. Our recent findings that COMP directly binds to zinc-metalloproteinase ADAMTS-7B (also designated COMPase), a newly identified member of the ADAMTS (a disintegfin and metalloprotease with thrombospondin motifs) subfamily, provide a foundation for our central hypotheses that ADAMTS-7B is the first identified physiological enzyme responsible for endogenous COMP degradation in arthritis. To test this central hypothesis, studies will be conducted addressing three specific aims: (1) to clone and characterize human ADAMTS7B; (2) to determine whether ADAMTS7B can cleave COMP and if so, what are the cleavage sites in COMP; and (3) to study naturally occurring inhibitors of ADAMTS-7B. The proposed studies will extend our understanding of the degradative events that occur in patients with arthritic disorders and provide us with the inhibitors designed to serve as therapeutics for the treatment of arthritis [unreadable] [unreadable]